Mechanisms of Diabetic Nephropathy

Abstract

D iabetic nephropathy is a major microvascular complication of diabetes, representing the leading cause of endstage renal disease in the Western world, and a major cause of morbidity and mortality in both type 1 and type 2 diabetic subjects. Clinical hallmarks of diabetic nephropathy include a progressive increase in urinary albumin excretion and a decline in glomerular filtration rate (GFR), which occur in association with an increase in blood pressure, ultimately leading to endstage renal failure. 1 These renal functional changes develop as a consequence of structural abnormalities, including glomerular basement membrane thickening, mesangial expansion with extracellular matrix accumulation, changes in glomerular epithelial cells (podocytes), including a decrease in number and/or density, podocyte foot process broadening and effacement, glomerulosclerosis, and tubulointerstitial fibrosis.Diabetic nephropathy occurs only in a minority of subjects with either type 1 or type 2 diabetes and seems to result from the interaction between genetic susceptibility and environmental insults, primarily metabolic and hemodynamic in origin. Over the last decade, the cellular and molecular mechanisms by which these insults translate to structural and functional abnormalities leading to diabetic nephropathy have been increasingly delineated. In particular, it has been determined that both metabolic and hemodynamic stimuli lead to the activation of key intracellular signaling pathways and transcription factors, thus triggering the production/release of cytokines, chemokines, and growth factors, which mediate and/or amplify renal damage.In the present review, we summarize molecular and cellular mechanisms that seem to be responsible for hypertensioninduced renal injury in diabetes, with particular focus on the role of increased intracapillary glomerular pressure, more recently discovered components of the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) 2, and the increasing knowledge that has been gained emphasizing cross-talk between metabolic and hemodynamic pathways in amplifying diabetes-related renal injury. Impact of Hypertension on Diabetic NephropathyThe relationship between hypertension and poor vascular outcomes, including progression of renal disease, is unequivocal and independent of other confounding factors. The impact of hypertension on outcomes is exponential rather than linear. A sustained reduction in blood pressure seems to be currently the most important single intervention to slow progressive nephropathy in type 1 and type 2 diabetes. Long-term follow-up studies of initially normotensive diabetic subjects without renal disease demonstrate a blood pressure-dependent decline in GFR with blood pressure levels within the reference range. 2 Patients with a blood pressure corresponding to Ͻ130/80 mm Hg rarely develop microalbuminuria and show an annual decline in GFR close to the age-matched normal population. Diabetic patients with a blood pressure between 130/80 and 140/90 mm Hg have ...

Increases in Central Aortic Impedance Precede Alterations in Arterial Stiffness Measures in Type 1 Diabetes

“…Evidence for microvascular damage is suggested by the correlation between increased Z c and urine albumin levels in our study. Increased glomerular perfusion pressure, as might be seen if pressure pulsatility increases, is known to lead to renal microvascular damage (30). Our data suggest that changes in the central aorta may precipitate renal microvascular change or, conversely, that early microvascular damage in the kidney may contribute to increases in pressure and flow pulsatility at all levels of the circulation.…”

Retinal Vessel Calibers Predict Long-term Microvascular Complications in Type 1 Diabetes: The Danish Cohort of Pediatric Diabetes 1987 (DCPD1987)

“…Hypertension is known to accelerate the progression of renal disease in patients with diabetes (29). In addition to the well-known association between narrow arteriolar calibers and coexisting hypertension (30)(31)(32), a meta-analysis and data pooling study showed that narrow retinal arteriolar calibers appear to precede clinical hypertension (33).…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…The impact of hypertension on outcomes is exponential rather than linear. 9 Even in normotensive diabetic patients, lowering blood pressure can be beneficial in controlling diabetic nephropathy and retinopathy. 10 In particular, in patients with type 2 DM, the risk of diabetic nephropathy and retinopathy was independently and additively attributable to hypertension and hyperglycemia.…”

“…10 In particular, in patients with type 2 DM, the risk of diabetic nephropathy and retinopathy was independently and additively attributable to hypertension and hyperglycemia. 6 Arterial hypertension is a main risk factor in the development and progression of diabetic nephropathy, 9 and a sustained reduction in blood pressure is probably the most effective single intervention to slow the progression of nephropathy in type 1 and type 2 DM. 7,[9][10][11] In the Wisconsin Epidemiology Study of DR, the presence of hypertension in type 1 diabetic patients was associated with a 73% increase in the risk of incident proliferative DR. 12 More recently, the Wisconsin Epidemiology Study of DR demonstrated that the 25-year incidence of visual impairment was related to poorer glycemia control and the presence of arterial hypertension.…”